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Glucose Intake and Utilization in Pre-Diabetes and Diabetes: Implications for Cardiovascular Disease
Glucose Intake and Utilization in Pre-Diabetes and Diabetes: Implications for Cardiovascular Disease
Glucose Intake and Utilization in Pre-Diabetes and Diabetes: Implications for Cardiovascular Disease
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Glucose Intake and Utilization in Pre-Diabetes and Diabetes: Implications for Cardiovascular Disease

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This important reference, edited by Ronald Ross Watson and Betsy Dokken, collects the research needed to make the distinct connection between pre-diabetes, diabetes, and cardiovascular disease. Glucose Intake and Utilization in Pre-Diabetes and Diabetes: Implications for Cardiovascular Disease explains the mechanisms of progression from pre-diabetes to diabetes to cardiovascular disease. Since pre-diabetes and diabetes are important cardiovascular disease risk factors, and impaired glucose metabolism among cardiac patients is extremely prevalent, the importance of reviewing pre-diabetes and its involvement in CVD complications is vital as one applies food and glycemic control to slow progress to diabetes and heart disease. The book further focuses on glucose intake and utilization in diabetes, including coverage of diabetes in the development and pathology of cardiovascular disease, risks and epidemiology of cardiovascular problems promoted by diabetes, macrovascular effects and their safety in therapy of diabetics, beta cell biology and therapy of diabetes, and nutrition to modulate diabetes.

  • Offers a complete review of cardiac health problems occurring with significant frequency in patients relative to their ability to regulate glucose
  • Presents coverage of the role of glucose utilization, development of pre-diabetes and the ultimate development of various cardiovascular diseases
  • Provides thorough dietary, nutrition, complementary and alternative botanical therapies for pre-diabetes and diabetes to halt the progression to cardiovascular disease
LanguageEnglish
Release dateNov 22, 2014
ISBN9780128005798
Glucose Intake and Utilization in Pre-Diabetes and Diabetes: Implications for Cardiovascular Disease

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    Glucose Intake and Utilization in Pre-Diabetes and Diabetes - Ronald Ross Watson

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    Part I

    Pre-Diabetes in Health and Disease: Prevention and Treatment

    Outline

    Section 1 Modulation of Pre-Diabetes and Altered Glucose Metabolism: Pathophysiology, Drugs, Genetics, Epigenetics, and Nutrition

    Section 2 Nutrition and Food to Modulate Pre-Diabetes and Resulting Cardiac Disease

    Section 1

    Modulation of Pre-Diabetes and Altered Glucose Metabolism: Pathophysiology, Drugs, Genetics, Epigenetics, and Nutrition

    Outline

    Section 1A Background on pre-diabetes and its management

    Section 1B Physiological modulators of pre-diabetes and cardiovascular disease development

    Section 1A

    Background on pre-diabetes and its management

    Outline

    Chapter 1 Early Origins of Health and Disease

    Chapter 2 Diabetes and Obesity: The Impact of Their Coincidence on Health and Life

    Chapter 3 Diabetes: A New Horizon and Approach to Management

    Chapter 4 Psychosocial Factors Associated with Diabetes Self-Management

    Chapter 5 The Relationship Between the Organization of Services for the Treatment of Type 2 Diabetes and the Risk of Long-Term Complications

    Chapter 6 Effects of Bariatric Surgery on Comorbid Conditions Associated with Morbid Obesity

    Chapter 7 Dietary Management of Pre-Diabetes and Type 2 Diabetes

    Chapter 1

    Early Origins of Health and Disease

    C. Yzydorczyk, PhD¹, D. Mitanchez, MD-PhD², F. Boubred, MD-PhD³ and U. Simeoni, MD¹,    ¹Division of Pediatrics & DOHaD Laboratory, CHUV University Hospital and UNIL, Lausanne, Switzerland,    ²Division of Neonatology, Department of Perinatology, Armand Trousseau Hospital, 75012 Paris & Sorbonne Universités UPMC University Paris 06, Paris, France,    ³Department of Neonatology, University Hospital, Marseille, France

    In the 1980s, David Barker and his colleagues proposed that the major causes of cardiovascular mortality in industrialized countries may have their roots in early development. They notably observed an association between birth weight and coronary heart disease mortality rates later in life. Further epidemiological, clinical, and animal experimental studies have suggested that the time period that extends from conception through pregnancy to early infancy, also mentioned as the first 1000 days, is a critical window for the programming of lifelong health or disease. During this period, environmental stimuli potentially lead to physiological malprogramming determining final health outcomes. We review here how the early exposure to factors such as maternal undernutrition, glucocorticoids, placental insufficiency, maternal diabetes/obesity, preterm birth, oxidative stress, and epigenetic modifications can set the scene for later hypertension, obesity, and type 2 diabetes, features of the metabolic syndrome and other noncommunicable diseases.

    Keywords

    Fetal programming; developmental origins of health and disease; low birth weight; premature birth; noncommunicable diseases; hypertension; obesity; type 2 diabetes; metabolic syndrome

    Chapter Outline

    Introduction 5

    Developmental Programming of MS (CVD): Human Data 6

    Excess Nutrients During Fetal Growth and Long-Term Consequences 6

    Mechanisms Underlying Fetal Overgrowth 6

    Effects of Maternal Gestational Weight Gain 6

    Consequences of Being Large at Birth 6

    Consequences of Exposure to Maternal Diabetes or Obesity In Utero 7

    Undernutrition During Pregnancy as a Cause of MS and CVD 8

    The Consequences of Being Small at Birth 8

    The Thrifty Phenotype Hypothesis 8

    Maternal Caloric Restriction: the Dutch Famine 8

    The Consequences of Preterm Birth 8

    Effects of Postnatal Nutrition and Catch-Up Growth 9

    Developmental Programming of MS (CVD): Animal Models 10

    Nutritional Modifications 10

    Proteins and Caloric Restriction 10

    Carbohydrates 11

    High-Fat Diet 11

    Neonatal Overnutrition and Catch-Up Growth 11

    Animal Models of Human Type 1 and 2 Diabetes 11

    Animal Models of T1D 11

    Animal Models of T2D 12

    Animal Model of Gestational Diabetes 12

    Uteroplacental Insufficiency 12

    Glucocorticoids Exposure 12

    Mechanisms 13

    Oxidative Stress 13

    Epigenetic Regulation 13

    DNA Methylation 13

    Histone Modifications 14

    Non-coding RNAs 14

    Conclusion 15

    References 15

    Introduction

    Cardiovascular diseases (CVD) and type 2 diabetes (T2D) are usually considered diseases of adult lifestyle. Smoking, high-energy and high-fat diets, and a lack of physical exercise, which lead to overweight, hypertension (HT), dyslipidemia, and impaired glucose regulation, are risk factors for both conditions. However, there is no doubt now that adult lifestyle is not the whole story. Since the 1980s, there is increasing evidence that the roots of these adult diseases may be triggered very early in life. The Developmental Origins of Health and Disease (DOHaD) hypothesis was originally put forward by David Barker and colleagues in Southampton in the United Kingdom. In the 1980s, they observed that low birth weight (LBW), an indirect clinical marker of inappropriate intrauterine development, was inversely correlated with the risk of HT in adult life and cardiovascular mortality in a large cohort of men and women born in Hertfordshire (UK) [1]. Thereafter, this association has been observed many times by epidemiological studies in different countries and populations all over the world [2–5]. LBW as a consequence of intrauterine growth restriction (IUGR) or as a consequence of preterm birth could be responsible for CVD later in life. Excessive weight at birth also exposes the child to later metabolic disorders and CVD in adults. Furthermore, the growth of children during early life could also have an important role in the mortality from CVD.

    Epidemiologic studies suggested the existence of a critical time window, from conception throughout pregnancy to early infancy, that is sensitive to long-lasting effects of environmental perturbations and therefore could potentially lead to physiological malprogramming determining final health outcomes. An exposition to certain factors during this vulnerability period, such as maternal undernutrition, glucocorticoids, placental insufficiency, maternal diabetes and obesity, and stress can set the scene for later HT, obesity, and T2D disorders, features of the metabolic syndrome (MS), and other chronic, noncommunicable diseases. The mechanisms by which exposure to altered intrauterine milieu or unsuitable early neonatal nutrition increases these risks are not fully understood. The contribution of animal models in the understanding of the mechanisms has been very important in the last years. Therefore, animal studies are critical for understanding the physiopathology of the developmental origins of adult diseases. Marked advances were also made in the last decade in deciphering the molecular mechanisms, particularly how external factors (nutritional or others) can impact the regulation and the function of genes without alteration of the genetic code.

    Developmental Programming of MS (CVD): Human Data

    Excess Nutrients During Fetal Growth and Long-Term Consequences

    The two main conditions during pregnancy that expose the fetus to excess of nutrients are maternal diabetes and obesity. Gestational diabetes mellitus (GDM) exposes the fetus to future diseases such as obesity, HT, renal diseases, and diabetes. Maternal obesity is also tightly linked with GDM or pre-existing T2D. The risk of GDM is 2.14-fold higher in overweight pregnant women, 3.56-fold higher in obese pregnant women, and 8.56-fold higher in severely obese pregnant women compared with pregnant women with normal weight [6].

    Mechanisms Underlying Fetal Overgrowth

    These two maternal conditions expose the fetus to overnutrition and subsequent overgrowth and macrosomia. The mechanisms of the impact of maternal diabetes and obesity on fetal and neonatal physiology are still incompletely understood. The Pedersen’s hypothesis, formulated more than 50 years ago, suggested that fetal overgrowth was related to increased transplacental transfer of maternal glucose, stimulating the release of insulin by the fetal beta-cells. Because insulin is the fetal growth factor, subsequent macrosomia occurs [7]. Indeed, different studies have characterized the link between maternal glycemia and neonatal macrosomia or fat mass [8]. Other inter-related mechanisms play a role in the modification of fetal nutrition and metabolism and may have an impact on the long-term outcome. In GDM, apart from hyperglycemia, maternal metabolic environment is characterized by insulin resistance (IR) and inflammation [9]. Both conditions increase placental availability of nutrients to the fetus, not only glucose but also amino acids and free fatty acids, and influence fetal growth. IR facilitates maternal hypertriglyceridemia that enhances substrate availability to the fetus. Other mechanisms influence nutrient supply to the fetus. The placental transcriptome has been shown to be a target of the altered environment of diabetic pregnancy. For example, genes for lipids transport have been shown to be up-regulated in the placenta of women with GDM, as are genes for inflammatory pathways [10,11]. Altogether, such alterations directly or indirectly change the availability of substrates, other than glucose, to the fetus either by increasing their source or by modifying the materno–fetal interface. Additionally, placental epigenetic changes were recently reported at gene loci involved in energy metabolism regulation like those of adipokines [12]. This epigenetic adaptation to detrimental in utero environment may have an impact on the short- and the long-term metabolic regulations of the newborn. Maternal pre-gestational overweight or obesity that is frequently associated to GDM or T2D may also increase lipid availability and modulate delivery of lipid substrates to the fetus. Indeed, it was shown that pre-pregnancy overweight/obesity increases the risk of macrosomia and subsequent offspring overweight and obesity [13]. The increase in birth weight (BW) in obese pregnancy is attributable primarily to an increase in the neonate’s fat mass, not in lean mass [14].

    Effects of Maternal Gestational Weight Gain

    The influence of maternal substrates on fetal growth is illustrated by the association between excess of gestational weight gain (GWG) with high BW. The comparison of differences in BW between sibling pairs showed that for every additional kilogram an individual woman gained during pregnancy, the BW of her offspring increased by about 25 g [15]. In a large prospective multicentric study, excessive GWG was an independent valuable predictor of macrosomia. In the subgroup of diabetic mother, excessive GWG (according to the Institute of Medicine [IOM] recommendations) was related to a 2.6-fold increased risk of developing macrosomia (aOR 2.6; 95% CI 1.2–5.5) [16]. In a large Swedish prospective cohort, offspring body mass index (BMI) was also associated with maternal GWG. However, in normal weight women, this positive association was only driven by shared familial risk factors for BMI (genetic/environment). In overweight and obese women, greater maternal GWG appears to be associated with greater offspring BMI shared not only via familial characteristics but also via intrauterine mechanisms [17].

    Consequences of Being Large at Birth

    A number of publications reported the link between high BW and obesity in childhood to early adulthood. A meta-analysis showed that BW ≥4000 g increases twofold the risk for obesity, and this risk is increased about 2.5-fold when BW exceeds the 90th percentile [18]. Being large for gestational age (LGA, BW >90th percentile) in association with GDM or maternal obesity increases the risk of MS in childhood, which is also mentioned as syndrome X and defined by an impaired glucose tolerance, HT, obesity, and dyslipidemia. A longitudinal cohort study analyzed the prevalence of MS in children aged 6–11 years; accordingly, they were LGA or adapted for gestational age (AGA, BW 10–90th percentile), and their mothers had or did not have GDM. The prevalence at any time of at least two components of MS was higher for the LGA/GDM group (50%), compared to the LGA/control group (29%), AGA/GDM group (21%), and AGA/control group (18%). The risk of developing MS with time was significantly different between LGA and AGA offspring in the GDM group, with a 3.6-fold greater risk among LGA children by 11 years. In this study, children exposed to maternal obesity were also at increased risk of developing MS [19]. The influence of maternal pre-pregnancy BMI on latter cardiometabolic risk was confirmed in a large longitudinal cohort study, including 1400 young adults at 32 years of age. Per each increase of 1SD in maternal pre-pregancy BMI, it was found an increase of 1.8 kg/m² in offspring BMI, and 1.7 and 1.1 mmHg in systolic and diastolic blood pressure (BP), respectively [20].

    A recent systematic review on the association between BW and risk of T2D showed that in most populations studied, BW was inversely related to T2D risk. There was a positive association between high BW (>4000 g) and risk of T2D only in two native North American populations. These populations have an exceptionally high prevalence of T2D and obesity from early ages, and a very high prevalence of GDM. Then, the influence of maternal diabetes/obesity on the BW–T2D association could not be excluded in these populations and may overweight the effect of being LGA alone [21].

    Consequences of Exposure to Maternal Diabetes or Obesity In Utero

    Extensive data on the consequences of exposure to diabetes in utero on childhood overweight and obesity and risk of T2D have been obtained from the Pima Indians studies. The Pima Indian population has an exceptionally high prevalence of obesity and T2D due to genetic reasons. The prevalence of T2D in offspring of Pima women increases up to sixfold in those with diabetic or pre-diabetic mothers, and diabetes during childhood and adolescence occurred almost exclusively among the offspring of diabetic and pre-diabetic mothers [22]. In the same way, the offspring born to mothers with pre-gestational T2D or GDM are heavier at birth and at every age than those born to non-diabetic mothers. There are some evidences that the greater frequency of diabetes and obesity in the offspring of diabetic Pima women are not due to genetic susceptibility to obesity and diabetes. Studies including sibling pairs in which one sibling was born before and the other was born after the onset of maternal diabetes have brought interesting data [23]. The risk of diabetes was significantly higher in siblings born after the mother developed diabetes than in those born before the mother’s diagnosis of diabetes (odds ratio 3.7, P=0.02) and the mean BMI was 2.6 kg/m² higher in offspring of diabetic than in offspring of non-diabetic pregnancies (P=0.003) [24]. Offspring of Pima mothers who had diabetes during pregnancy also had higher systolic blood pressure (SBP) than offspring of mothers who did not develop T2D until after pregnancy. This was independent of the levels of adiposity [25].

    These results were confirmed in other ethnic groups. Gillman et al. have shown that 9.7% children overweight at early adolescence were born to mothers with GDM compared with only 6.6% if the mother was without GDM [26]. In a large prospective Swedish cohort, BMI of men whose mothers had diabetes mellitus during their pregnancy was on average 0.94 kg/m² greater at age 18 (95% [CI], 0.35 to 1.52) than in their brothers born before their mother was diagnosed with diabetes, after adjustment for maternal age, parity and education [17]. When compared with offspring not exposed to maternal diabetes, exposed offspring have a worse cardiovascular risk profile with the increased levels of circulating cellular adhesion molecules, which are biomarkers of adverse endothelium perturbation. These markers are related to the earliest preclinical stages of atherosclerosis and diabetes [27]. Epidemiological studies that focused on BP values in the adult offspring of mothers with GDM found a low increase in SBP. A recent systematic review confirmed the association between exposure to maternal diabetes and SBP in childhood. But this association was significant only in male offspring. Furthermore, there is some evidence that this association may be influenced by maternal pre-pregnancy BMI [28].

    The longitudinal cohort study EPOCH (Exploring Perinatal Outcome among Children) found that youths exposed to maternal GDM had a higher average BMI growth trajectory from 27 months through 13 years of age, and higher BMI growth velocity starting at age 10–13 years. But no differences were noted in growth velocity until 26 months of age [29]. The long-term effects of in utero exposure to diabetes should extend beyond neonatal and early childhood periods and emerge during puberty, a sensitive period for the development of glucose intolerance and obesity.

    The parental BMI seems to play an important role in the development of cardiometabolic risk in childhood. A higher maternal and paternal pre-pregnancy BMI were associated with an increase in adiposity levels and an adverse cardiometabolic profile in their children. Associations of maternal pre-pregnancy BMI with childhood outcomes tended to be stronger compared with associations of paternal BMI [30], notably concerning the increased SBP [31].

    Accumulating evidence suggests that maternal diabetes and/or overweight/obesity are associated with increased risk of obesity and CVD in offspring, at any age from early childhood. However, there remain many unanswered questions regarding the size effect of intrauterine exposure compared with shared genetic traits. These are also difficult to distinguish from the influence of a child’s postnatal environment and lifestyle.

    Undernutrition During Pregnancy as a Cause of MS and CVD

    Also, fetal malnutrition will affect fetal development and might have lasting consequences for the offspring. One of the obvious parameters of poor fetal nutrition is LBW. In the last three decades, there has been a huge increase in literature exploring the relation between LBW and adult diseases in humans.

    The Consequences of Being Small at Birth

    Barker and his co-workers were the first to mention the existence of an association between LBW and higher risk of death from CVD. The data from an English survey of 1586 men born in a maternity hospital in Sheffield during 1907–1925 showed that death rates from CVD fell progressively with increasing weight, head circumference, and ponderal index (weight/length³) at birth [1]. In the Hertfordshire cohort, including 5654 men born during 1911–1930, death rates from coronary heart disease were almost three times higher among those who weighed 8.2 kg or less at 1 year of age than among those who weighed 12.3 kg or more [32].

    The association between BW and the development of MS in adult life was also shown. The prevalence of MS was 10 times higher in the subjects with a BW less than 2.95 kg as compared with those whose BW was greater than 4.31 kg [33].

    Afterwards, many epidemiological studies confirmed this association between LBW and the increased risk of MS as a whole [34–36], or an association with components of MS [37] as HT [38], impaired glucose tolerance and IR [39,40] or dyslipidemia [41–43] and obesity [44,45].

    The Thrifty Phenotype Hypothesis

    Based on these data, Barker suggested the origins of CVD or other noncommunicable diseases lay partly in the effect of undernutrition during critical periods of development during fetal and early postnatal life [46]. In the fetal programming hypothesis, he proposed that fetal undernutrition could occur for a variety of reasons, including poor maternal diet or problems with the transfer of nutrients from mother to fetus as a consequence of a disruption of placental blood flow causing insufficient uteroplacental perfusion. The fetus adapts to this threatening environment, limiting his growth and prioritizing the development of essential tissues. This concept, known as the thrifty phenotype hypothesis, proposed that when the fetal environment is deficient of an essential factor or includes a harmful factor, the fetus adapts by favoring growth of crucial organs such as the brain and the heart at the expense of other organs such as the pancreas, liver, and skeletal muscle that have reserve capacity and are considered less important for survival under these adverse environmental conditions [47]. This developmental plasticity induces structural and functional abnormalities in pancreatic beta-cells and leads to abnormal insulin sensitivity. It may also alter renal differentiation and reduce nephron number in adults, paving the way for later HT [48]. These adaptations would confer a survival advantage in a nutritionally deprived environment, predicted by the poor intrauterine environment. But if the postnatal environment does not match the predicted one (as observed in occidental societies), the excess of food may not be tolerated by the organism. These adaptations enable short-term survival but permanently change the body’s physiology, structure, and metabolism, and may influence cardiovascular and metabolic health in later life as a trade-off (Figure 1.1).

    Figure 1.1 Mismatch between the developmental programming induced by adverse early environment and the influence of later environmental clues.

    Maternal Caloric Restriction: the Dutch Famine

    The most convincing illustration of maternal caloric restriction and development of adult metabolic diseases came from Dutch famine studies. During the 1944–1945 famine, the daily ration officially provided to an individual was 400–800 calories, even for pregnant women. Exposure to famine during any stage of gestation was associated with glucose intolerance. Coronary heart disease, atherogenic lipid profile, increased stress responsiveness, and obesity were found more frequently at adulthood among those exposed to famine in early gestation. Women exposed to the famine during mid- to late gestation had babies with significantly reduced BW. Babies whose mothers were exposed only during early gestation had normal BW; however, they grew up to have higher rates of obesity than those born before and after the war and higher rates than those exposed during mid- to late gestation. Thus, although reduced BW is the most easily measured proxy for intrauterine deprivation, it is not by itself the cause of later adult disease as mentioned above, and it does not always accompany the types of exposure that lead to adult disease [49].

    The Consequences of Preterm Birth

    LBW is not only the consequence of IUGR but could also be associated with preterm birth. Epidemiological studies have described long-term health consequences of prematurity, apart from physical and neuro-developmental disabilities. As compared with young adults who had been born at term (gestational age (GA) comprised between 37.0 and 42.9 weeks), it has been shown that preterm birth with very LBW (<1500 g; GA ranged from 24.0 to 35.6 weeks) had significantly higher fasting insulin, 2-h insulin, and 2-h glucose concentrations, as well as a higher HOMA-IR index and higher BP. These differences were not attributable to body size or fat distribution [50]. This data suggested that preterm birth seems to be associated with signs of IR and impaired glucose regulation in early adulthood. Furthermore, a systematic review and meta-analysis have examined the role of shortened gestation on SBP. The mean GA at birth of the preterm participants was 30.2 weeks (range: 28.8–34.1 weeks), BW was 1280 g (range: 1098–1958 g), and age at SBP measurement was 17.8 years (range: 6.3–22.4 years). Former preterm or very low birth weight (VLBW) infants had higher SBP than term infants (pooled estimate: 2.5 mm Hg [95% CI: 1.7–3.3 mmHg]). These results suggest that preterm and VLBW infants have a slightly higher SBP later in young adult life than those born at term, but they may be at increased risk for developing HT and its sequelae later in life [51]. In preterm infants, artificial nutritional intakes replace physiological placental nutrients delivery during the first weeks of life. The quality of these postnatal nutrients may not be suitable for the immature organism and for future health. This was in particular illustrated in a randomized trial comparing preterm infant assigned human milk versus formula for just 4 weeks. In this study, marked benefits of human milk were observed at 13–16 years old on BP, lipids profile, and IR [52].

    Effects of Postnatal Nutrition and Catch-Up Growth

    There is much evidence in the literature that an early accelerated postnatal growth or a rapid postnatal catch-up growth during infancy enhances the risk of obesity and CVD at adulthood.

    Faster early growth acceleration is also associated with biochemical CVD risk factors such as IR in term infants with both normal or LBW [53,54]. Later IR was also greater in adolescents born preterm with accelerated growth in the first 2 weeks [55]. Such growth was also associated with greater endothelial dysfunction: Those with the greatest early weight gain had 4% lower flow mediated endothelial-dependent dilatation of the brachial artery, compared with those with the least early weight gain [56].

    Indeed, one of the predictions made by the DOHaD is that fetal adaptations to scarcity become maladaptive only when affected individuals are later exposed to an environment of plenty. This is dramatically shown by comparing those exposed to the Dutch Hunger Winter with babies born after the siege of Leningrad. In both cases, pregnant women were exposed to severe famine. However, whereas The Netherlands returned to a complete diet quite quickly after the time of severe restriction, there were continuing shortages in the USSR, where those exposed to famine in utero did not exhibit higher rates of either obesity or CVD as adults [57]. It should be emphasized that those exposed to the Dutch Hunger Winter during late gestation (i.e., were born a few months into the famine) were also exposed during early infancy, whereas those exposed during early gestation (i.e., near the end of the famine) were born several months after the war when diets had improved.

    The critical window period is not well defined and early growth may correspond to a spectrum that spans between the first 2 weeks to the first 2 years at least. It was shown that greater weight gain in the first week of life can program obesity in adulthood: each 100 g increase in absolute weight gain during this period was associated with an increase of 28% in the risk of being overweight (95% CI 8–52%) [58]. It has been suggested that breastfeeding has benefit effects for long-term obesity because the pattern of growth is slower among breastfed infants compared to formula fed [59]. A long-term advantage of breastfeeding was further supported by a dose–response effect. A longer duration of breastfeeding was associated with lower tendency to later obesity; each month of breastfeeding was associated with a decrease of 4% (95% CI −6% to −2%) in obesity risk [60]. Breastfed babies may control the amount of milk they consume and so learn to self-regulate their energy intake better than those given formula, although whether this difference persists into adult life is unknown. Nutritional benefits of breastfeeding may include differences in nutrients between human milk and formulas (lower glucose and protein, concentrations in long-chain polyunsaturated fatty acids). Differences in early protein intakes that are greater in formula than in human milk could also affect later adiposity.

    Furthermore, it has been shown that slow growth before birth and accelerated postnatal growth (catch-up growth) during the first weeks or months of life are associated with the emergence of glucose intolerance, IR, T2D, and an increased risk of being overweight or obese in childhood and in early adult life. Individuals at greatest risk have an earlier pre-pubertal adiposity rebound and gain weight faster in the late pre-pubertal period. Notably, Eriksson showed in a longitudinal study (8760 subjects born in Helsinki during 1934–1944) that the incidence of T2D decreased progressively from 8.6% in persons whose adiposity rebound occurred before the age of 5 years to 1.8% in those in whom it occurred after 7 years, which was preceded by low weight gain between birth and 1 year [61].

    LBW babies seem to be more vulnerable. In a large British study it has been shown that LBW babies, who were the most at risk to develop obesity, were light and thin at birth and then experienced a period of rapid growth in the first 7 years of life [45]. It has been observed that at birth, infants with LBW have lower circulating insulin and Insulin-like Growth Factor-1 concentrations. By 48 hours after birth, they are more insulin-sensitive and have higher plasma free non-esterified fatty acid. Thereafter, they undergo a period of accelerated postnatal growth, which is associated with increased insulin sensitivity. This early period of increased insulin sensitivity and accelerated growth precedes the subsequent development of metabolic diseases later in life, notably the IR [62,63].

    Growth velocity also seems to be important in cases of excessive growth at birth, particularly in infants born from diabetic mothers. Adequate breastfeeding (≥6 months) reduces in childhood the increase of adiposity levels associated with exposure to diabetes in utero [64]. Furthermore, these results were strengthened by the follow-up of a longitudinal cohort. It was shown that adequate breastfeeding reduces the overall body size and slows BMI growth velocity both during infancy as well as in the childhood period, in offspring of non-diabetic mothers, as well as in offspring of diabetic mothers. These effects were independent of sex, race/ethnicity, current childhood diet, and physical activity levels. This study indicates that the favorable effects of breastfeeding on BMI growth patterns extend throughout the entire childhood period and are also present in youth at increased risk for obesity due to intrauterine exposure to maternal diabetes [65]. Others have reported data that favor the benefit of breastfeeding in offspring of diabetic mothers, either on the risk of obesity [66] or on the risk of diabetes [67]. Therefore, encouraging diabetic mothers to breast-feed could be a good way to ensure a long-term protective effect on the offspring.

    Nutrition in early life and infancy is a challenge for pediatricians. In the developed environment, fast weight gain in LBW and preterm infants should probably be avoided, as well as, poor early growth in macrosomic babies should be accepted. The best way to attain such a goal is to encourage maternal breastfeeding and optimizing nutrition later in infancy, while monitoring growth.

    Developmental Programming of MS (CVD): Animal Models

    Nutritional Modifications

    Proteins and Caloric Restriction

    Many studies have used dams (rats and mice in the major studies) fed during pregnancy and/or lactation with a low protein diet (LPD, between 8% and 9% of the food composition instead of the normal amount, about 18–20%, while keeping the diet isocaloric). Detrimental effects have been mentioned in offspring from LPD dams characterized by a LBW, a decrease in number of pancreatic cells and nephrons, IR. Consequently, this leads in adulthood to HT and renal diseases, T2D [68–73] and it is also associated with a decrease in lifespan [74]. Severe caloric restriction during gestation leads to LBW and increased BP later in life [75]. It has been shown that postnatal hypercaloric nutrition amplifies the metabolic disorders induced by fetal undernutrition, with the development of hyperinsulinism, hyperleptinemia, and obesity [76]. Whereas, postnatal caloric restriction superimposed to IUGR seems to be protective and to improve the metabolic profile [77].

    Carbohydrates

    The relation between protein/carbohydrate intakes during gestation and the development of MS in offspring is complex. Low carbohydrate intakes were associated with IUGR [78] and with an increase of BP when combined with high protein intakes [79]. Exposure to high levels of fructose during pregnancy and lactation can also lead to increased fasting insulin at weaning [80] and thereafter increased leptin and glucose levels [81] that promote obesity in offspring [82].

    High-Fat Diet

    Nowadays, consuming a high-fat diet (HFD) is a characteristic of the eating habits of the developing and westernized societies. Using animal models, it has been shown that HFD administrated during pregnancy and lactation leads to the development of hypercholesterolemia [83], adiposity, IR, and HT at different stages of life [84]. The development of MS is more amplified if HFD is also administrated in the adulthood period [85,86]. An increase of macronutrient intakes can have a detrimental effect on offspring. High protein and fat intakes during pregnancy may impair development of the fetal pancreatic beta-cells and so lead to insulin deficiency in the offspring in adulthood [87]. An obesogenic diet (high fat and high sugar) administrated during pregnancy and lactation leads to adiposity, IR, and HT later in life [84]. It has been proposed that an imbalance between oxidant/antioxidant resulting in higher oxidative stress (OS) could be one of the mechanisms responsible for the detrimental effect of HFD [88]. OS alters fatty acid and therefore may inhibit both glucose oxidation and its ability to enter into cells [89]. Also, HFD impairs the glucose signaling system of the beta-cell and the capacity of insulin secretion, therefore leading to a decrease of beta-cell mass and an increased apoptosis [90].

    Neonatal Overnutrition and Catch-Up Growth

    Early postnatal overfeeding allowed rapid postnatal catch-up growth but accelerated the development of cardiometabolic diseases and decreased the lifespan [74]. One rodent model to induce neonatal overnutrition is the reduction of the litter size. The purpose is to give a surplus of milk for each offspring [91]. Thereafter, these animals displayed hyperphagia, overweight, hyperinsulinemia, glucose intolerance, increased triglycerides levels, and SBP [76,92,93] and these effects are amplified in IUGR offspring [76]. Also, an early neonatal overfeeding following IUGR accelerates the development of renal disease [94]. One possible mechanism involved in the development of the adipogenic and diabetogenic phenotype could be the epigenetic alterations. Notably, the existence of a neonatal alteration of DNA methylation inside the promoter region of gene coding for proopiomelanocortin, which is the most important anorexigenic neurohormone, involved in the control of appetite, body weight, and metabolism has been shown [95].

    Animal Models of Human Type 1 and 2 Diabetes

    Experimental models are developed with the purpose of enhancing the understanding of the pathophysiological mechanisms of diseases that affect humans, notably type 1 diabetes (T1D) and T2D. Resulting diabetes has been described in many animal species (sheep, pig, and rabbit). However, rodents are the experimental models used most because of the short length of pregnancy and multiparity [96–99].

    Animal Models of T1D

    T1D in humans is characterized by a specific destruction of the pancreatic beta-cells, commonly associated with immune-mediated damages [100].

    Surgical Models

    In rodents, after puberty, the partial pancreatectomy (removal of 95% of pancreatic weight) leads to a decrease of beta-cells number and therefore to the development of uterine placental defects and fetal alterations associated with mild maternal diabetes (glycemia between 150 and 200 mg/dL). Insulin administration is not required and, thereafter, the pregnancy rates are normally good. However, the post-surgery mortality is relatively elevated (20%) and there is a delay (2–3 months) between the surgical procedure and the development of diabetic symptoms [101].

    Chemical Model

    In general, the human T1D is reproduced by streptozotocin (STZ) administration to rats during adult life [102]. STZ is a nitrosourea derivative isolated from Streptomyces achromogenes [103]. It is a powerful alkylating agent that has been shown to interfere with glucose transport [104] and glucokinase function [105], and able to methylate DNA. Nevertheless, it is generally accepted that the cytotoxicity produced by STZ depends on DNA alkylation [106]. The beta-cells of the islets of Langerhans express high levels of GLUT-2 transporters but also have a relatively low nicotinamide adenine dinucleotide content, therefore making them more vulnerable to STZ toxicity [107]. Different modes of injection and different doses are mentioned: intravenous or intraperitoneal and 30–50 mg/kg. Also, STZ administration can be performed in pre-gestational or gestational period, which leads to the development of a severe or mild diabetes associated with IUGR or macrosomic fetus. In cases of mild diabetes, mothers are hyperglycemic (values comprised between 120 and 300 mg/dL) and hypoinsulinemic, leading to macrosomic fetuses. Whereas, in cases of severe diabetes, mothers are insulin deficient and hyperglycemic, leading to small fetuses (characterizing IUGR) and to congenital malformations [108].

    Spontaneous Animal Models

    The Non-Obese Diabetic (NOD) mice and Bio-Breeding (BB) rats develop spontaneous pre-gestational diabetes. The beta-cells are subjected to immune attack by T-, B-cells, macrophages, and natural killer cells being recruited to the insulitis [109].

    NOD Mouse

    NOD mice develop a mild form of diabetes characterized by macrosomic fetuses and adiposity. Also, an insulitis is present at 4–5 weeks old, followed by beta-cell destruction and a decrease in circulating insulin concentrations. Mild diabetes is present between 12 and 30 weeks of age. However, insulin-dependent diabetes develops spontaneously only in 9% of NOD at 12 weeks of age and in 80% of them by 30 weeks of age [110]. In contrary to human T1D, ketoacidosis is relatively mild and affected animals can survive for weeks without insulin injection.

    BB Rat

    BB rats are a good model for the study of perinatal morbidity, macrosomia, and congenital malformations. Compared to NOD, but in common with human T1D, BB rats model develop severe diabetes and ketoacidosis that can be fatal if exogenous insulin is not administered [111].

    Animal Models of T2D

    T2D represents a heterogeneous group of disorders characterized by IR, impaired insulin secretion, and defined by a raised fasting or post-challenge blood glucose.

    Production of Spontaneous Diabetic Rats

    Goto Kakizaki (GK) is a rodent model of non-obese T2D [112,113]. This strain was developed by the successive inbreeding of Wistar rats with the administration of highest blood glucose concentrations [114]. GK rats develop some features that can be compared with the complications of diabetes observed in humans, such as renal lesions [115], structural changes in peripheral nerves [116], and abnormalities of the retina [117]. GK offspring exposed throughout gestation to mild diabetes present a severe reduced beta-cell mass associated with a lack of pancreatic reactivity to glucose that seems to be the consequence of a reduction in cell proliferation, defective IGF signaling pathways, and increased apoptosis in the fetal pancreas [118,119].

    Chemical Model

    Human T2D is reproduced in rodents by administration of different doses of STZ (80–100 mg/kg) in the neonatal period [120]. The timing of the neonatal STZ injection seems to be important to the degrees of severity of the subsequent diabetic state. It has been shown that the effects observed in adulthood were more important if STZ was administrated 5 days after birth [121] compared with an administration on the day of birth [122]. In fact, STZ administrated 5 days after birth leads in adulthood to the development of a frank basal hyperglycemia and glucose intolerance, an increase of glycosylated hemoglobin, a strong decrease of pancreatic insulin stores, a reduction (50%) of basal plasma insulin level, and a default of plasma insulin response to glucose in vivo [123]. This difference of timing could be explained by the fact that the pancreatic insulin stores recovered due to the regeneration of the beta-cells after the STZ insult [124].

    Animal Model of Gestational Diabetes

    Leprdb/+ (db/+) mice, which present an autosomal recessive mutation in the leptin receptor, provide a gestational diabetic animal model. During gestation, db/+ dams present hyperphagia, gain more weight, and have hyperleptinemia compared with wild type dams. Also, during gestation, insulin and glucose tolerance tests are abnormal. Their offspring are heavier at birth [125].

    Uteroplacental Insufficiency

    In animal models, the most common procedure to induce artificial placental dysfunction in rat offspring is bilateral uterine artery ligation during late gestation of dams. Their offspring have an LBW and decreased number of nephrons and cardiometabolic alterations with increasing age. At 10 weeks of age, it has been reported that they have IR and glucose intolerance; at 6 months of age, they have a decrease of beta-cells mass [126]; at 12 months, they have an increased SBP [127]; and, at 18 months, they have an increase of proteinuria [128], plasma triglycerides, and leptin levels [129].

    Glucocorticoids Exposure

    An increase in circulating glucocorticoids (GC) during a critical window of development plays a role in early programming of renal diseases, HT, glucose intolerance, and IR in the offspring [130–133]. It is well established that exposure to excess GC alters the fetal hypothalamic–pituitary–adrenal (HPA) axis, and so could be one of the mechanisms that may explain the relation between LBW and the development of MS in adulthood. Protein and caloric restriction, respectively, in rats and sheep leads to the decrease of 11β-hydroxysteroid dehydrogenase type 2 (11-βHSD-2) activity and therefore exposes the fetus to high maternal GC levels [134,135]. In rodents, increased GC exposure can permanently reduce the pancreatic beta-cell mass and decrease pancreatic insulin levels and therefore contributes to increased risk of metabolic disease later in life [136]. Also, administration of dexamethasone (exogenous GC) or 11β-HSD-2 inhibitor, carbenoxolone, to pregnant rats reduced the 11β-HSD-2 activity, led to LBW, programmed HT, hyperglycemia, hyperinsulinemia, renal damage [71,137,138], and hyperactivity of the HPA axis later in life [139], which can persist to the second generation [140]. Phosphoenolpyruvate carboxykinase (PEPCK) plays an important role in hepatic gluconeogenesis. Prenatal exposure to dexamethasone leads to increased activity and levels of PEPCK, therefore predisposing to glucose intolerance in adulthood [132].

    Mechanisms

    Oxidative Stress

    OS may be the link between impaired fetal growth or preterm birth and later elevated risks of MS, T2D, and CVDs [19]. Many known factors such as preeclampsia, diabetes, obesity, smoking, malnutrition or excessive nutrition, infection, or inflammation are associated with LBW and preterm birth, and are considered as pro-oxidative conditions [141–145]. Endogenous antioxidant enzymes as superoxide dismutase (SOD), catalase, glutathione peroxidase and reductase, and vitamins are necessary for the detoxification of deleterious ROS [146]. Premature babies are notably more susceptible to OS notably because of lower levels of antioxidants, as vitamin A, C, and E [147]. In animal models, protein malnutrition is associated with a depressed antioxidant defense system (glutathione peroxidase and SOD activities) and an increase of lipid peroxidation (malondialdehyde levels) [148]. Cambonie et al. demonstrated that in an LPD-exposed (containing 9% casein) rat fetus, creating LWB offspring, the level of glutathione (ubiquitous cellular antioxidant) is decreased, and the administration of lazaroid (peroxidation inhibitor) to the pregnant dams concomitantly with the LPD prevented the elevation of BP and vascular dysfunction observed in the offspring at adulthood [149]. In another animal model, maternal protein restriction leads to an age-associated increase of OS level characterized by an increase of lipid peroxidation (hexanoyl lysine adducts), a decrease of antioxidant defenses (heme-oxygenase, SOD), and an increase of markers of islet fibrosis (collagen I and III), which can lead to progressive beta-cell loss and dysfunction [150]. LBW followed by accelerated postnatal growth is associated with impaired antioxidant defenses (SOD expressions) and increased markers of senescence (p21 and p16) in beta-cells of the pancreatic islets [151]. The reduction of uteroplacental blood flow in rat leads in offspring to increased production of reactive oxygen species (ROS), and a default in ATP generation, therefore perpetuating the cycle of mitochondrial dysfunction that could also damage the beta-cells and lead to altered insulin secretion [152].

    Moreover, an increase of lipid peroxidation levels and protein oxidative damage have been observed in the erythrocytes of both mothers with gestational diabetes and their newborn infants [153]. It is well documented that in diabetes as well as in macrosomia, protein glycation and glucose auto-oxidation may generate free radicals, and therefore catalyzed lipid peroxidation [154]. Also, T2D in human and in experimental animal model is accompanied by an alteration in antioxidant enzymes activities [155], impaired glutathione metabolism [156], and decreased ascorbic acid levels [157].

    Epigenetic Regulation

    Epigenetic modifications can be defined as changes in the pattern of gene expression without involving changes in the sequence of DNA. The fetal environment can alter the epigenome of the offspring and therefore leads to different phenotypes [158–160]. Three main pathways can silence, activate, or regulate the level and time of expression of many genes: DNA methylation, histone modifications (acetylation, methylation, ubiquitination, phosphorylation, or ADP-ribosylation), and small non-coding RNAs, such as microRNAs (miRNAs) [161,162]. In general, these three epigenetic mechanisms appear to work together to regulate gene expression. DNA methylation or histone modifications can alter the expression of miRNAs, which can in turn regulate the expression level of DNA methyltransferases, histone methyltransferases, histone deacetylases, and methyl CpG-binding proteins, therefore regulating the epigenetic processes of DNA methylation and histone modifications [161].

    DNA Methylation

    It is the best-known pathway and usually leads to repression of transcription of the involved gene. Methylation takes place on CpG islands mainly located in the promoter region of the genes. Usually, if these islands of the promoter region are unmethylated the gene is transcribed, but when a significant part of the CpG islands are methylated the gene can no longer be transcribed and is silenced. In early life, DNA methylation can be altered by many nutritional factors such as folate, choline, betaine, methionine, and vitamins B2, B6, and B12 (methyl donors) [163]. Therefore, this DNA modification can affect the development and thus the risk of developing cardiometabolic diseases later in life. Epigenetic marks are particularly vulnerable during the very early stage of development [164]. In the Dutch Famine study, exposure to famine only in the periconceptional period was associated with lower methylation of insulin-like growth factor 2 (a key factor in human growth and development and is maternally imprinted) [165] six decades later [166]. In another study, a greater methylation of retinoid X receptor-α and endothelial nitric oxide synthase was associated with greater adiposity in later childhood, suggesting the role of epigenetic alterations in fetal programming of later metabolic outcomes [167]. On the other hand, in animal models of maternal protein restriction, the promoter of the angiotensin II receptor type-1b gene in the adrenal-gland [168], and of GCs receptor [169] are significantly hypomethylated, leading to an increase in their expression. These modifications may represent one of the mechanisms involved in the programming of HT observed in these animal models.

    Histone Modifications

    In the nucleus of eukaryotic cells, DNA is coiled around octamers of globular proteins called histones, forming dense blocks of DNA and proteins named nucleosomes and which in conjunction form chromatin, the condensed form of DNA. Histones can be modified on the tails by methylation, acetylation, phosphorylation, biotinylation, ubiquitination, and ADP-ribosylation [160,161]. These modifications facilitate or obstruct the access to DNA of transcription factors and together with the other epigenetic factors regulate gene expression.

    In a rodent model of IUGR that expressed a lower level of Pdx1 (a transcription factor critical for beta-cell function), epigenetic modifications characterized by loss of upstream stimulatory factor-1 binding at proximal promoter of Pdx1, recruitment of histone 1 and the corepressor Sin3A, and deacetylation of histone H3 and H4 were observed. This resulted in Pdx1 silencing that persisted from 2 weeks to 4 months of age and was responsible for pre-diabetic state in the rats [170]. Maternal HFD in primates leads to impaired lipid metabolism in the fetus and is correlated with an increase of histone H3 acetylation and a decrease of histone deacetylase activity [171]. Histone modifications were also proposed to decrease the expression of glucose transporter-4 (glycoprotein that facilitates glucose transport which is involved in the development of glucose intolerance) in the IUGR offspring. Such alterations persist at adulthood and could be an adaptive response to the decrease of insulin pancreatic production [172].

    Non-coding RNAs

    miRNAs are small single-strand RNA that do not encode proteins. Each miRNA binds to specific messenger RNAs (mRNAs), resulting in degradation of target mRNA or inhibition of its translation into protein. miRNAs regulate the post-transcriptional expression level of many genes and processes such as apoptosis, cell growth, and differentiation in a large range of tissues. Therefore, miRNAs are involved in many processes including angiogenesis, cardiogenesis, nephrogenesis and related diseases [173,174]. miRNAs are critical regulators of metabolism. It has been shown that miR-103, miR-107, and miR-33 regulated insulin sensitivity and glucose homeostasis [175–177]. Two circulating miRNAs (let-7 g and miR-221) have a female-specific elevation in individuals with MS [178]. Concerning the features of MS, blood miR-197, miR-23, and miR-509-5p positively correlated with BMI, and elevated circulating miR-130a and miR-195 were associated with high BP [179]. Also, an over-expression of miR-143 was involved in default of insulin-stimulated AKT (also known as protein kinase B) and glucose homeostasis [180].

    A comprehensive understanding of the early origins of health and disease may thus involve a sequential relationship between innate and acquired factors. The genome may determine an increased risk for noncommunicable disease at adulthood by the way of at-risk genetic polymorphisms. The environment within which the individual is exposed during the particularly sensitive window of early development, is responsible for epigenetic marks upon the genome, which translate the influence of environmental nutrition, or exposure to toxicants and/or endocrine disruptors (Figure 1.2).

    Figure 1.2 Sequence involving the genome, the epigenome, and interactions between innate and acquired environmental influences to explain the early origins of health and disease.

    Conclusion

    As illustrated in this review, early-life exposure to varying environmental factors during a crucial period of development can lead to the development of cardiometabolic diseases later in life. This underlines the importance for the physicians who take care of the fetus and young infants to be aware of such consequences. Indeed, the most efficient way to face the current worldwide pandemic of obesity and diabetes is probably to develop preventive measures early in life. However, such measures will have a huge impact only if they are stemming from a genuine policy of health sustained by the different governments. At the same time, scientific research should be encouraged, as animal models have enabled during the last few years a better understanding of physiopathology of the developmental origins of adult diseases. Among the different mechanisms, the epigenetic alterations and notably the miRNAs may represent an interesting pathway to identify populations at risk to develop these pathologies, particularly among LBW and preterm infants.

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